The ability to deliver pharmaceutical agents into and through skin surfaces (transdermal delivery) provides many advantages over oral or parenteral delivery techniques. In particular, transdermal delivery provides a safe, convenient and noninvasive alternative to traditional administration systems, conveniently avoiding the major problems associated with oral delivery (e.g. variable rates of absorption and metabolism, gastrointestinal irritation and/or bitter or unpleasant drug tastes) or parenteral delivery (e.g. needle pain, the risk of introducing infection to treated individuals, the risk of contamination or infection of health care workers caused by accidental needle-sticks and the disposal of used needles).
However, despite its clear advantages, transdermal delivery presents a number of its own inherent logistical problems. Passive delivery through intact skin necessarily entails the transport of molecules through a number of structurally different tissues, including the stratum corneum, the viable epidermis, the papillary dermis and the capillary walls in order for the drug to gain entry into the blood or lymph system. Transdermal delivery systems must therefore be able to overcome the various resistances presented by each type of tissue.
In light of the above, a number of alternatives to passive transdermal delivery have been developed. These alternatives include the use of skin penetration enhancing agents, or “permeation enhancers,” to increase skin permeability, as well as non-chemical modes such as the use of iontophoresis, electroporation or ultrasound. However, these alternative techniques often give rise to their own unique side effects such as skin irritation or sensitization. Thus, the spectrum of agents that can be safely and effectively administered using traditional transdermal delivery methods has remained limited.
More recently, a novel transdermal drug delivery system that entails the use of a needleless syringe to fire powders (i.e., solid drug-containing particles) in controlled doses into and through intact skin has been described. In particular, commonly owned U.S. Pat. No. 5,630,796 to Bellhouse et al. describes a needleless syringe that delivers pharmaceutical particles entrained in a supersonic gas flow. The needleless syringe is used for transdermal delivery of powdered drug compounds and compositions, for delivery of genetic material into living cells (e.g., gene therapy) and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The needleless syringe can also be used in conjunction with surgery to deliver drugs and biologics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). In theory, practically any pharmaceutical agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using such devices.
To enable powdered drug compositions to be effectively administered via this new needleless syringe technique, the powders should have certain physical characteristics. In particular, the size of the particles which form the powders should be controllable, preferably with a narrow size distribution. Further, the particle density should be high, the particles should be free-flowing under a dry environment and their moisture content should be low. Additional properties of the particles which are desired include a spherical shape and a smooth surface. Each of these properties is important to provide good skin penetration whilst avoiding damage to the particles themselves under the forces required for delivery via needleless syringe.
One of the most important factors in determining the physical characteristics of the powders is the particular manner by which they are produced. Various spray freeze-drying techniques have previously been described for, for example, the preparation of powders for aerosol delivery and microspheres for conventional drug delivery. In these applications, particles are desired to be light and porous, properties which are inherent in powders produced by previously described spray freeze-drying techniques. Such light and porous particles are not suitable for use in needleless syringe devices.
Maa et al. (1999) Pharmaceuticals Research 16(2) describe the physical characteristics of spray-freeze-dried particles and their performance as aerosols. The spray freeze-drying process is said to render highly porous particles with a large specific surface area. Maa estimated that the particle density of spray freeze-dried particles is typically approximately one ninth of that of equivalent particles dried by spray-drying.
U.S. Pat. No. 5,019,400 describes a process for preparing microspheres using very cold temperatures to freeze polymer-biologically active agent mixtures into polymeric microspheres with retention of biological activity and material. Polymer is dissolved in a solvent together with an active agent that can be either dissolved in the solvent or dispersed in the solvent in the form of microparticles. The polymer/active agent mixture is atomised into a vessel containing a liquid non-solvent, alone or frozen and overlayed with a liquified gas, at a temperature below the freezing point of the polymer/active agent solution.
When the combination with the liquified gas is used, the atomised droplets freeze into microspheres upon contacting the cold liquified gas, then sink onto the frozen non-solvent layer. The frozen non-solvent is then thawed. As the non-solvent thaws, the microspheres which are still frozen sink into the liquid non-solvent. The solvent in the microspheres then thaws and is slowly extracted into the non-solvent, resulting in hardened microspheres containing active agent either as a homogeneous mixture of the polymer and the active agent or as a heterogeneous two phase system of discrete zones of polymer and active agent.
If a cold solvent is used alone, the atomized droplets freeze upon contacting the solvent, and sink to the bottom of the vessel. As the non-solvent for the polymer is warmed, the solvent in the microspheres thaws and is extracted into the non-solvent, resulting in hardened microspheres.